Treatment of serious infections due to MDR Acinetobacter baumannii : - - PowerPoint PPT Presentation

Treatment of serious infections due to MDR Acinetobacter baumannii : Presentation of a multicenter randomised clinical trial

Riccardo Utili Professor of Internal Medicine and Infectious Diseases Department of Cardiothoracic and Respiratory Sciences University of Naples – Monaldi Hospital Italy

• R. Utili - Disclosures

Speaker activity for Novartis, MSD, Pfizer Research support: Novartis, MSD, Pfizer

Difficulties in planning therapeutic trials for A. baumannii infections

• A. baumannii infections (especially VAP) usually occurs late in the

course of a severe disease (multiple comorbidities) in the ICUs Thus, patients may die for the Acinetobacter or with the Acinetobacter. Crude mortality rate is high (40-60%) Attributable mortality is a clinical judgment (risk of assessment bias) it can only be estimated in a case control study Need of strong outcomes to get reliable results , i.e.,

• 30 day mortality (including later f-u or out of hospital events)
• microbiological data collected at predetermined times
• lenght of hospitalisation

Porins

Efflux Pumps

Aminoglycoside modifying enzymes (AMEs)

aminoglycosides

(Oxa; Imp; VIM)

• A. baumannii: a ‘successful pathogen’

Imipenem - Meropenem (not Aztreonam)

Fq, B-lactams, CAF, macrolides, sulfamides trimetoprim, tetraciclines

Adapted from Limanski JCM 2002; Urban CID 2003

AmpC B- lactamase

Cefalosp 1-2-3 gen Ampicillin aztreonam

Loss of OMP (outer membrane proteins) – USA & Europe

Integrons for MDR

MexAB-OprM

VIM-IMP-OXA-ESBL-MEX-OPR

Plasmides - Europe PBP2 alteration

(hyperproduction in 50% of isolates)

Only option available

COLISTIN

• It acts by altering membrane permeability
• Poor lung diffusion
• Nephrotoxic
• Overall low efficacy when used as monotherapy
• Treatment is largely empiric

Antibiotic combinations as an alternative approach to colistin monotherapy

Tripodi MF, Utili R et al. Int J Antimicrob Ag 2007

1 2 3 4 5 6 7 8 9 10

Log10 (viable cells) CFU/mL

Time (h)

CT RIF COL COL + RIF

0 4

Co.R.A.b. study

Colistin vs Colistin+Rifampicin in A.baumannii infections Open label, parallel, randomized 5 clinical sites, 210 pts enrolled (2008-2011)

(Funded by the Italian Medicines Agency, AIFA; ClinicalTrials.gov number, NCT01577862).

Utili R., Durante-Mangoni E., et al. under evaluation

INCLUSION EXCLUSION CRITERIA CRITERIA

• Age >18 y
• ICU admission
• Life-threatening infection

(HAP, VAP, BSI, cIAI)

• Positive A.baumannii cultures
• XDR antibiotype
• Strain susceptible to colistin
• Previous

treatment with colistin or rifampicin

• Hypersensitivity

to either study drug

• Significant liver dysfunction

(serum conjugated bilirubin >3 mg/dl).

Co.R.A.b. study

Colisitin vs Colistin+Rifampicin in A.baumannii infections

Utili R., Durante-Mangoni E., et al. under evaluation

Typical antibiogram

Treatment arms

Colistin monotherapy

• Colistimethate sodium
• 2 MU (=160 mg), q8h, i.v.
• Treatment duration: 10-21 d.

Colistin + Rifampicin combination

• Colistimethate sodium, same dose
• Rifampicin, 600 mg q12h, i.v.
• Treatment duration: 10-26 d.

Co.R.A.b. study

Randomization

• Centre site
• Simplified Acute Physiology Score (SAPS) II <40 or ≥40

Utili R., Durante-Mangoni E., et al. under evaluation

Acinetobacter baumannii infection CENTRAL RANDOMIZATION

• CENTRE
• SEVERITY OF

ILLNESS COLISTIN, 2MU TID COLISTIN, 2MU TID RIFAMPIN, 600 MG BID

t0 EoT EoS t0 EoT EoS 10-21 days

t0: baseline; EoT: end of treatment; EoS: end of study;

COLISTIN AND RIFAMPICIN FOR XDR-ACINETOBACTER

21 4 7 11 14 10-21 days 21 4 7 11 14

The study was designed to identify an absolute mortality reduction

• f 20%.

Assuming a raw 30-day mortality rate of 60% in the control group, a two-tailed significance level of 0.05, a power of 0.8, an allocation ratio of 1:1 and a drop-out rate of 10%, 207 patients had to be enrolled (East software v. 4).

Sample size

Primary end point

30-day crude mortality (death for any cause within 30 days from randomization)

Co.R.A.b. study

Secondary end points

• disease-specific death
• microbiological eradication
• hospitalization length
• emergence of resistance to colistin during treatment

Utili R., Durante-Mangoni E., et al. under evaluation

Safety evaluation

Co.R.A.b. study

• renal dysfunction possibly related to colistin
• neurotoxicity, possibly related to colistin
• hepatic dysfunction, possibly related to rifampicin

Utili R., Durante-Mangoni E., et al. under evaluation

The end